Fracture healing is a complex process that involves the sequential recruitment of cells and the specific temporal expression of factors essential for bone repair. The fracture healing process begins with the initial formation of a blood clot at the fracture site. Platelets and inflammatory cells within the clot release several factors that are important for chemotaxis, proliferation, angiogenesis and differentiation of mesenchymal cells into osteoblasts or chondroblasts.
The fracture healing process subsequent to the initial hematoma formation can be classified as primary or secondary fracture healing. Primary fracture healing occurs in the presence of rigid internal fixation with little to no interfragmentary strain resulting in direct bone formation across the fracture gap. Secondary fracture healing occurs in response to interfragmentary strain due to an absence of fixation or non-rigid fixation resulting in bone formation through intramembranous and endochondral ossification characterized by responses from the periosteum and external soft tissue.
Intramembranous bone formation originates in the periosteum. Osteoblasts located within this area produce bone matrix and synthesize growth factors, which recruit additional cells to the site. Soon after the initiation of intramembranous ossification, the granulation tissue directly adjacent to the fracture site is replaced by cartilage leading to endochondral bone formation. The cartilage temporarily bridging the fracture gap is produced by differentiation of mesenchymal cells into chondrocytes. The cartilaginous callus begins with proliferative chondrocytes and eventually becomes dominated by hypertrophic chondrocytes. Hypertrophic chondrocytes initiate angiogenesis and the resulting vasculature provides a conduit for the recruitment of osteoblastic progenitors as well as chondroclasts and osteoclasts to resorb the calcified tissue. The osteoblastic progenitors differentiate into osteoblasts and produce woven bone, thereby forming a united fracture. The final stages of fracture healing are characterized by remodeling of woven bone to form a structure, which resembles the original tissue and has the mechanical integrity of unfractured bone.
Studies have documented that diabetes impairs bone healing clinically and experimentally due to low insulin levels. For example, a novel intramedullary insulin delivery system was used in a diabetic femur fracture model to investigate the potential direct effects of insulin on bone healing. (See Gandhi, A., et al., “The effects of local insulin delivery on diabetic fracture healing,” Bone, vol. 37(4), pp. 482-90 (2005).) However, Gandhi et al. does not rule out the possible normalization of blood glucose levels or reduction of advanced glycation endproducts (byproduct of hyperglycemia) in the local fracture environment. The use of a diabetic fracture model prevents a definitive conclusion from being reached regarding the anabolic effects of insulin.
A further study by Cornish, J., et al., “Insulin increases histomorphometric indices of bone formation in vivo,” Calcif. Tissue Int., vol. 59(6), pp. 492-5 (1996), uses a non-diabetic intact calvarial animal model to investigate the effects of insulin on bone metabolism. However, the processes of bone metabolism are vastly different from bone repair. Bone metabolism is the interplay between bone formation and bone resorption. Bone repair, as described previously, is a complex process that involves the sequential recruitment and the differentiation of mesenchymal cells towards the appropriate osteoblastic/chondrogenic lineage to repair the fracture/defect site.